My project is to investigate whether the enhancement of intrinsic beta cell defense mechanisms protects against oxidative stress-induced cell damage. To reach this objective my study will address the following specific aims: Aim 1. Determine the effect of pancreatic beta cell-specific overexpression of the antioxidant enzyme glutathione peroxidase on diabetes development and progression in an animal model of spontaneous type 2 diabetes, the diabetic db/db mouse. Aim 2. Determine whether pancreatic beta cellspecific overexpression of the antioxidant enzyme glutathione peroxidase in db/db mice results in the protection of beta cells from damage induced by chronic hyperglycemia. Aim 3. Determine whether pancreatic beta cell-specific overexpression of the antioxidant enzyme glutathione peroxidase results in protection of the beta cells against abnormalities that are characteristically found with declining beta cell function due to chronic exposure to hyperglycemia. These include decreased expression of the insulin and PDX-1 genes and MafA protein. The experiments will be conducted in a rodent model of type 2 diabetes, the db/db mouse. We will compare glutathione peroxidase transgenic and wild type mice for the incidence, time of onset and severity of the disease, and relate these parameters to the functional capacity of the beta cells determined by their secretory activity, plasma insulin levels, pancreatic insulin content, and glucose tolerance. We will determine the extent and duration of preservation of pancreatic beta cell mass by morphometry and relate this to the structural organization of the islets, cellular composition, and beta cell apoptosis rate. Pancreases and isolated islets from transgenic db/db and control wild type animals will also be analyzed for expression and subcellular localization of insulin, PDX-1, and MafA genes and protein. We hypothesize that enhancing endogenous pancreatic beta cell antioxidant defense will protect against beta cell damage due to oxidative stress caused by chronic exposure to hyperglycemia and, hence, will provide a better preservation of the pancreatic beta cell mass and function, resulting in the delay or prevention of the worsening of the disease in this model of type 2 diabetes. Relevant findings will help design future studies aiming to preserve pancreatic beta cells and delay or prevent type 2 diabetes through use of antioxidant drugs in type 2 diabetic patients and subjects with impaired glucose tolerance. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: The objective of my study thus relates to the National Institute of Health mission to acquire new knowledge to help prevent, detect, diagnose, and treat disease, and improve human health through biomedical and behavioral research, research training and communications. [unreadable] [unreadable] [unreadable]